A Phospholipid-Derived Nanotherapeutic Platform for Improved Colorectal Cancer Immunochemotherapy

用于改进结直肠癌免疫化疗的磷脂衍生纳米治疗平台

基本信息

批准号：
10658146
负责人：
Jianqin Lu
金额：
$ 34.51万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10658146
关键词：
Antineoplastic Agents Blood Circulation Blood Circulation Time Camptothecin Cancer Etiology Cancer Model Cancer Patient Cells Cessation of life Charge Clinic Clinical Clinical Trials Colorectal Cancer Combined Modality Therapy Cytotoxic T-Lymphocytes Development Disulfides Doxorubicin Doxorubicin Hydrochloride Liposome Drug Kinetics Drug Modelings Encapsulated Goals Hydrophobicity Immune Immune checkpoint inhibitor Immune response Immunity Immuno-Chemotherapy Immunocompetent Immunosuppression In Vitro Interferon Type II Kinetics Lactones Length Lipid Bilayers Liposomes Maximum Tolerated Dose Measures Mediating Memory Microsatellite Instability Mismatch Repair Deficiency Monoclonal Antibodies Mus PD-1 blockade PD-1 inhibitors PD-1/PD-L1 Pathway interactions Patients Pharmaceutical Preparations Phospholipids Regimen Regulatory T-Lymphocyte Safety Secure Series Solubility Structure-Activity Relationship System T-Cell Proliferation T-Lymphocyte Technology Testing Therapeutic Therapeutic Agents Tissues Toxic effect Translating Transportation Treatment Efficacy Tryptophan Tryptophan 2,3 Dioxygenase Tumor Immunity Up-Regulation Vertebral column amphiphilicity anti-cancer antitumor effect cancer cell cancer therapy cancer type chemotherapy clinical application colon cancer patients effector T cell fortification hydroxyl group immune checkpoint immune checkpoint blockade immunogenic immunogenic cell death improved in vivo inhibitor innovation liposomal delivery nanotechnology platform nanotherapeutic novel pi bond response screening self assembly side effect standard of care success systemic toxicity tumor tumor eradication uptake

项目摘要

Project Summary/Abstract While immune checkpoint inhibitors (ICIs) have transformed the landscape of cancer treatment paradigm, the response rate is limited to a small subset of cancer patients (~20%). For colorectal cancer (CRC), the second leading cause of cancer-related deaths in US, only patients (~4%) with mismatch-repair-deficient or microsatellite instability-high tumors can respond to ICIs, leaving the vast majority of CRC patients with limited to no clinical benefit. Chemotherapy has been increasingly manifested to contribute significantly to the overall antitumor efficacy when combined with ICIs via switching the tumors from “immune-cold” to ‘immune-hot’. However, owing to the poor solubility and pharmacokinetics, limited tumor accumulation, and non-specific toxicities to healthy tissues, the utility of chemotherapeutics in enhancing the efficacy of ICIs has been considerably hindered. To render a safer and more efficacious chemotherapy-enabled immune response to cooperate with ICIs, our long- term goal is to develop an innovative and multifunctional liposomal nanotherapeutic platform via conjugating anticancer agents to the backbone phospholipid of liposome. We have developed a phospholipid-derived camptothecin (CPT) liposome (Camptothesome) nanoplatform, which significantly prolonged blood circulation time, enhanced tumor uptake and therapeutic efficacy and minimized systemic toxicities compared to free CPT. Moreover, Camptothesome potentiated the anti-CRC efficacy of PD-L1/PD-1 inhibitors, resulting in partial eradication of tumors in immunocompetent mice. To improve the efficacy of this combined therapy, we used Camptothesome to co-deliver an inhibitor targeting another independent immune checkpoint, Indoleamine 2,3- dioxygenase (IDO1), which markedly enhanced anti-CRC efficacy and immunity. To further strengthen the delivery efficiency and explore the potential of this nanoplatform in enhancing PD-L1/PD-1 blockade therapy, in this proposal we will: Aim 1: Improve the Camptothesome system for enhanced therapeutic delivery. Aim 2: Determine the tumor delivery efficiency and pharmacokinetics of the improved co-delivery system in murine CRC models. Aim 3: Define antitumor effects of the improved co-delivery system with or without PD-L1/PD-1 blockade in murine CRC models. The mechanistic action for the in vivo antitumor efficacy and immune responses of the combined therapy will also be elucidated. Successful completion of this proposal will result in an innovative and multifunctional nanotherapeutic platform for improved and safe CRC immunochemotherapy. Moreover, given that IDO1 is expressed in diverse cancer cells, and the broad applicability of this nanoplatform to other anticancer drugs, our combination nanotherapeutic system has the potential to revolutionize cancer treatment paradigms.

项目概要/摘要虽然免疫检查点抑制剂（ICIs）已经改变了癌症治疗模式的格局，对于结直肠癌 (CRC)，缓解率仅限于一小部分癌症患者 (~20%)。在美国，癌症相关死亡的主要原因只有错配修复缺陷或微卫星的患者（约 4%）高度不稳定的肿瘤可以对 ICI 产生反应，从而使绝大多数 CRC 患者无法获得临床治疗越来越多的证据表明化疗对整体抗肿瘤有显着贡献。与 ICI 联合使用时，可将肿瘤从“免疫冷”转变为“免疫热”，从而发挥功效。溶解度和药代动力学较差、肿瘤积累有限以及对健康的非特异性毒性组织中，化疗药物在增强 ICI 疗效方面的效用受到了相当大的阻碍。提供更安全、更有效的化疗免疫反应，与 ICI 配合，我们的长期长期目标是通过缀合开发一种创新的多功能脂质体纳米治疗平台我们开发了一种以脂质体骨架磷脂为基础的抗癌剂。喜树碱（CPT）脂质体（Camptothesome）纳米平台，可显着延长血液循环与游离 CPT 相比，时间更长，肿瘤摄取和治疗效果增强，全身毒性最小化。此外，Camptothesome 增强了 PD-L1/PD-1 抑制剂的抗 CRC 功效，导致部分为了提高这种联合疗法的疗效，我们使用了免疫功能正常的小鼠中的肿瘤根除。 Camptothesome 共同递送针对另一个独立免疫检查点吲哚胺 2,3- 的抑制剂双加氧酶（IDO1），显着增强抗CRC功效和免疫力，进一步加强。递送效率并探索该纳米平台在增强 PD-L1/PD-1 阻断治疗方面的潜力，根据该提案，我们将：目标 1：改善 Camptothesome 系统以增强治疗效果。目标 2：确定改进的共递送系统的肿瘤递送效率和药代动力学在小鼠 CRC 模型中。目标 3：确定改进的联合递送系统在有或没有 PD-L1/PD-1 阻断的情况下的抗肿瘤作用在小鼠结直肠癌模型中的体内抗肿瘤功效和免疫反应的机制作用。还将阐明联合疗法，该提案的成功完成将带来创新和成果。用于改进和安全的 CRC 免疫化疗的多功能纳米治疗平台。 IDO1 在多种癌细胞中表达，以及该纳米平台在其他抗癌药物中的广泛适用性我们的组合纳米治疗药物系统有可能彻底改变癌症治疗模式。